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Abstract Lamins are nuclear intermediate filament proteins with diverse functions, ranging from organizing chromatin and regulating gene expression to providing structural support to the nucleus. Mammalian cells express two types of lamins, A-type and B-type, which, despite their similar structure and biochemical properties, exhibit distinct differences in expression, interaction partners, and function. One major difference is that A-type lamins have a significantly larger effect on the mechanical properties of the nucleus, which are crucial for protecting the nucleus from cytoskeletal forces, enabling cell migration through confined spaces, and contributing to cellular mechanotransduction. The molecular mechanism underlying this difference has remained unresolved. Here, we applied custom-developed biophysical and proteomic assays to lamin-deficient cell lines engineered to express specific full-length lamin proteins, lamin truncations, or chimeras combining domains from A- and B-type lamins, to systematically determine their contributions to nuclear mechanics. We found that although all expressed lamins contribute to the biophysical properties of the nuclear interior and confer some mechanical stability to the nuclear envelope, which is sufficient to protect the nuclear envelope from small cell-intrinsic forces and ensure proper positioning of nuclear pores, A-type lamins endow cells with a unique ability to resist large forces on the nucleus. Surprisingly, this effect was conferred through the A-type lamin rod domain, rather than the head or tail domains, which diverge more substantially between A- and B-type lamins and play important roles in lamin network formation. Collectively, our work provides an improved understanding of the distinct functions of different lamins in mammalian cells and may also explain why mutations in the A-type lamin rod domain cause more severe muscle defects in mouse models than other mutations. 

Abstract SummaryNetwork biology is an interdisciplinary field bridging computational and biological sciences that has proved pivotal in advancing the understanding of cellular functions and diseases across biological systems and scales. Although the field has been around for two decades, it remains nascent. It has witnessed rapid evolution, accompanied by emerging challenges. These stem from various factors, notably the growing complexity and volume of data together with the increased diversity of data types describing different tiers of biological organization. We discuss prevailing research directions in network biology, focusing on molecular/cellular networks but also on other biological network types such as biomedical knowledge graphs, patient similarity networks, brain networks, and social/contact networks relevant to disease spread. In more detail, we highlight areas of inference and comparison of biological networks, multimodal data integration and heterogeneous networks, higher-order network analysis, machine learning on networks, and network-based personalized medicine. Following the overview of recent breakthroughs across these five areas, we offer a perspective on future directions of network biology. Additionally, we discuss scientific communities, educational initiatives, and the importance of fostering diversity within the field. This article establishes a roadmap for an immediate and long-term vision for network biology. Availability and implementationNot applicable.